Flavone-7-oxy-acetamides



Oct.- 3, 1961 J. KLosA FLAVONE-'-OXY-ACETAMIDES Filed March l0, 1960 l llll Il l Lwmwmmw INVENTOR lse/f /Qosa BY MM ATTORNEY 3,002,979 FLAVONE-7-0XY-ACETAMIDES Josef Klosa, Berlin-Zehlendorf, Germany, assignor to Delmar Chemicals, Limited, Lachine, Quebec, Canada, a corporation of Canada Filed Mar. 10,1960, Ser. No. 14,079

` 7 Claims. (Cl. 260-345.2)

The present invention relates to novel flavone-7-oxyacetamides of the following formula:

wherein R and R1 may be H, lower.v alkyl groups of l-4 carbon atoms which, with the nitrogen atomy lalso form a ring system selected from piperidine, morpholine and pyrrolidine rings. Such a ring may also carry alkyl substituents. R Iand R1 may also :be aryl groups and` alkyl or alkoxy substituted aryl groups as for example pethoxyphenyl. They may stand also -for aralkyl groups, such as benzyl or phenylpropyl. When R'or R1 is alkyl, such alkyl group may be a straight or branched chain group. It may also carry substituents, so that R and R1 may also be hydroxyethyl-, 1.2-dimethyletbanol-(1), dimethylaminoethyl, diethylaminopropyl, and so forth. It was found that these compounds can be prepared by the following methods:

A. Flavone-7-oxy-acetic acid inthe form of areactive derivative may be reacted with an amine. A l

B..A ilavone-7-oxy-acetyl halide may be reacted with an amine.

amine.

D. A 7-oxy-avone or an alkaline salt thereof may be reacted with a halogen acetamide of the formula C. rA flavone-7-oxy-acetic ester may be reactedv with an in which formula R and R1 have the same signicance as When 7-oxy-flavone is ,used as the starting material,

(method D) the reaction maybe carried out in the presence of an alkali carbonate and acetone, toluol, benzol,

xylol, alcohols, dioxane may be used as solvents. The

halogen acetamide may be a ch1oro, 'bromo, or iodoacetarnide, but for economic reasons the chloro-acetamides are preferred. The addition of a small amount of alkali-bromide or iodide furthers and speeds up the reaction. .y t., y When a flavone-oxy-acetyl-halogenide (method B) or ester (method C) is reacted with an'amine 'the reaction may be carried out in or without the presence. of a -solvent or diluent. As flavone-oxy-acetyl-esters, themethyl-ethyL, propyl-, or generally speaking the esters of lower alcohols may Abe used. To speed up the reaction, catalytic amounts of alkaline metals may be added to the reaction. As flavone-oxy-acetyl-halogenides, the chloride and bromide are usefuh4 i j Flavone-7-oxy-acetic-alkanolesters and flavone-'I-oxyf acetic-alkanolamine-esters are known (BritishI Patent 803,372). These esters appear to provide afgood coronary-'dilating activity and a low toxicity-fA However,

their activity is of short duration, presumably because ICC they are rapidly hydrolyzed to the much less active and less vsoluble flavone-7-oxy-acetic acid.

To be therapeutically use-ful it is important that the activity .be sustained.

The compounds of the present invention have the following advantages:

(a) Low toxicity.

(b) Excellent cardio-therapeutic activity, combatting cardiac insufficiency particularly by the coronary-dilatiug ability'and in particular the ability to dilate the cardiac arteries.

(c) Good stability in the sense that they undergo practically no hydrolysis under physiological conditions.

The following experiment reinforces the above:

When 3 gms. of one of the compounds described in British Patent 803,372 and 3 gms. of one of the compounds described in the present invention are kept in an aqueous alcoholic solution, or in an aqueous suspension at room temperature, it will be found that the .esters are hydrolyzed after a few hours, whereas the amides prepared `according to the present invention can be recovered unchanged. The following table `sets forth the companative activity of khellin, avone-7-oxy-acetic ethylester (British Patent 803,372) and two of the compounds of the present invention:

. LDan in Coronary- Name of Compound Code No. mgJkg.' dilating activity Kham K 16o 1 I FlaoneJ-oxy-acetic acid ethyl- Fla 1 3, 200 14 es er. n Flavone- 7-oxy-acetic aeld amde Fla 2 4, 860 16 Flavone-7-oxy-aeetic acid N-dl- Fla 5 3,650 20 Y ethylamide.

The determination of the toxicity was done intraperitonically in white mice. The coronary-dilating activity was determined according to the method described by Langendortf (Peugers Archiv., vol. 61, p. 219 (1895)) as modiiied by Morawitz and A. Zahn (Zbl. Physiol., vol. 26,p..465 (1912)).

'I'he protracted and steady activity of the new compounds of the present invention can be easily demonstrated on the coronary ilow. Comparing two typical compounds:

' Flavone-7-oxy-acetic acid-(iN-beta-dimethylamino)-ethylester hydrochloride (Fla 30) and Flavone-7-oxy-acetic acid-(beta-diethylamino-ethylene) amide (Fla 20).

We find that both are well soluble in water. They are `both dissolved in a Ringer-Locke solution in a concentration of A4 mg./L. The coronary flow was measured in an. experimental setup according to Langendorif-Morawitz. The curves represent the average of 5 experil ments. The solutions were tried:

' (a) Fresh-used immediately after having been prepared; vand (b) after standing 5 days. Before testing the solutions were stirred in a constant temperature bath atV 37 for two hours.

In the curves the abscissa gives the time in minutes ofthe perfusion (on the isolated heart tissue), while the ordinate represents the coronary flow in ml./min.

It is obvious that Fla 20 has avery much greater and also a more prolonged activity.

In the following examples some of the compounds of the present invention Kare more fully described.

i Y Y 1 Example 1 Flavone-7-oXy-acetamide (method D) V (R=R1=H) Patented Oct. 3, 1961 11.9' gms. 7-oxy-iiavone, 7 gms. chloro-acetamide and 10 gms. anhydrous potassium carbonate are stirred and heated to reflux with 250 ml. acetone for 8 hours. The mixture is allowed to cool and stand for 4 hours, the supernatant liquid is poured oi and from this solution the acetone is removed by distillation. The residue of this operation is added to the solids left behind after the supernatant is decanted and the joined solids are stirred with 200 m1. water at room temperature. Much goes into solution. This aqueous suspension is filtered, the precipitate washed with water and then recrystallized from alcohol. Yield about 80%. M.P. 243-245 C.

From the aqueous filtrate some unreacted 7-oxy-lav0ne may be recovered by acidifying. The compound is Mcroanalyss.-Theory: C, 69.15%; H, 4.40%; N, 4.74%. Found: C, 69.24%, H, 4.38%; N, 4.92%.

Example 2 Flavone-7-oXy-acetyl-(N-phenylisopropyl)-amide (method D) 5 gms. of the sodium salt of 7-oxy-avone are reuxed in 30 m1. toluol for 4 hours with 4.2 gms. chloro-acetyl- (N-phenylisopropyl)amide. After this reuxing period the solution is filtered hot. To the ltrate some petroleum ether is added. The new amide crystallizes. The. product can be recrystallized from alcohol. M.P. 167- 169 C.

From the solids, which were filtered off at the end of the reaction, an additional quantity of the product can be obtained by treatment with water. The overall yield is about 85%. The compound is C26H23O4N.

Mcranalyszs.-Theoryz C, 75.54%; H, 5.56% N, 3.38%. Found: C, 75.61%; H, 5.51%; N, 3.45%.

Example 3 Theory Found Prepared as described in Example 3 by reacting the sodium salt of 7-oxy-avone with chloro-acetyI-(p-oxyphenyD-amide. M.P. 20S-205 C. Alcoholic solutions of this compound discolor on standing. The compoundv iS C23H17O5N.

Found N,v 3.70%

Example Flavone-7-oxyacetylantipyrine(4)-amide (method D).

R=H; riporta-42:0-

om-N how The compound is prepared similarly to Example 3 from the sodium salt of I-oxy-auone. and; 4.-('chioro-- acetyD-antipynine-amide. This compound may be re- 4 crystallized from propylene glycol. M.P. 243-245 C. The compound is CzHzONa.

Theory N, 8.73% Found N, 8.84%

Example 6 (a) Flavone-T-QXY-acetyl-diethylamide (method C) (R`'R1=C2H5`) 6.2 gms. iavone-7-oxy-acetic ethylester and 6 ml. diethylamine are reuxed for 6 hours in 50 m1. anhydrous methanol. The solution is then concentrated to half its volmue, diluted with water and acidied. The desired compound precipitates as a white crystalline powder. It

(c) Flavone-7-oxy-acetyl-N-morpholine-amide (R and R, forming a morpholine ring with `the N atom). M.P. 180-182 C.:

CzxHisOsN Theory N, 3.86% Found N, 3.92%

(d) F1avone--oxy-acetyl-N-piperidine-amide (R and R1 forming a piperidine ring with the N atom). MP. 198200 C.:

C22H2104N- Theory N, 3.85%

Found N, 3.89%

(e) Flavone7oxyacetylN-pyrrolidino-amide (R and R1 forming a -pyrrolidino ring with the N atom). M.P. 210 C.:

C21H1904N Theory N, 4.01% FOllIld N, 4.14%

(f) Flavone 7 oxy acetyl (2,2,6,6tetramethylpipcr lian-amid@ (R and, R1 forming a tetra-methyl substitilted Piperidiue ring with the N atom). MJ. 226 C.:

CaeH2s04N' Theory C, 76.28%; H, 7.15%; N, 3.42% Found C, 76.31%; H, 7.13%; N, 3.50%

CzsHznOlN Theory N, 3.52% `Found N, 3.74%

(h) Flavone-7-oxy-acetyl-mono-iso-butylamide (R=H; Ihm'sobutyh) Ml?. 168-470." C.:

C21H`2104N Theory N, 4.10% Found N, 4.24%

Example 7 (a) Flavone-7-oxy-ethanolamide (methodC) (R=H; R,=HocH,.cH,-3

3.2 gms. avone-7-oxy-acetyl-fethylester are relhnred with 2 ml. mono-ethanolamine in 30 ml. methanol. After the first 30 minutes already long, wla'te needle crystals separate. The reaction is complete after an hour. Yield about 85%. M.P. 20S-210 C.:

CinHl'zOsN v Theory 'C, 67.10%; H, 5.01%; N, 4.10% Found C, 67.28%; H, 5.08%; N, 4.31%

(b) Similarly there was prepared (using diethanolamine instead of mono-ethanolamne) the -lavone-'7-oiryacetyl-diethanolamide (R=R1=HOCH2CH2). .M.P. 14S-150 C.:

CnHziOeN Theory N, 3.65% Found N, 3.76%

Example 8 Flavone oxy acetyl beta (1.2 dimethyl) ethanolamide (method C) 1.2 gms. avone-7oxyacetylmethylesten 1 ml. 124imethylethanolamine and 20 ml. methanol are reuxcd for 3 After standing lfor two days, white crystals deposit. M.P. 164-165 C. -Upon diluting the mother Jliquor with water and .making it mildly acid, additional quantities are obtained. Total yield 85%:

CnHnOsN Theory N, 3.81% Found N, 3.88%

Example 9 3.5 gms. avorio-7-oXy-acetyl-n-propylester and 4 ml. N- methylaminoethanol are reuxed for 4 hours in 40 m1. alcohol. 'Ihe alcohol is removed by distillation. The remaining oil is taken up in a little fresh alcohol and diluted with water. The solution is neutralized with diluted hydrochloric acid. After several days standing, tine needles crystallize. M.P. 244-246 C. Yield about 3.2 gms.:

CaoHmOsN Theory N, 3.96% Found N, 4.02%

(b) In a similar way was prepared the flavone-7-oxyacetyl-N-ethyl-(beta-oxyethyl)amide:

CziHnOsN Theory N, 3.81% Found N, 3.97%

Example 10 (a) Flavone-7-oxy-acetyl-(nor-ephedrine)amide (method 3 gms. avone-7-oxy-acetyl-ethylester and 2 gms. d.l nor-ephedrine base are reuxed with 40 ml. methanol for eight hours. Upon cooling and after addition of some water, and acidification with diluted hydrochloric acid to pH 2-3, crystals result which may be recrystallized from alcohol. M.P. 13G-132 C. The compound is CzeHaaOsN- 6 Mcroanalysis: Theory: C, 72.72%; H, 5.36%; N, 3.26%. Found: C, 72.81%; H, 5.41%; N, 3.31%.

In the same manner there were prepared: (b) Flavone-7-oxyacetyl- (gammapropanol) amide (R=H, R1=HOCH2CHgCHr-). M.P. 186-188 C.

CzoHiaOsN Theory N, 3.97% Found N, 4.05%

CzoHlaOx-N Theory N, 3.97% Found N, 3.92%

CzlHzdosN Theory N, 3.85% Found N, 3.98%

CzsHasOtNz Theory C, 71.87%; H, 6.77%; N, 7.29% Found C, 71.90%.; H, 6.71%; N, 7.33%

This compound is a base since .it has a tertiary amino group and so is capable of forming salts. The following were prepared:

(b) HydrochIoride.-By dissolving the product in alcohol, adding alcoholic hydrochloric acid and some ether. M.P. 226-228 C. Very well soluble in water.

(c) Methyliodde.-By dissolving the base in alcohol and adding methyliodide, after a short while white crystals deposit. M.P. 22S-225 C.:

Cz4H2a04Nzl Theory N, 5.31%; I, 22.49% Found N, 5.37%; yI, 22.16%

Example 12 (a) Flavone 7 oxy acetyl (gamma cyclo hexylaminopropyl) amide (method C) (R=H; R1=C6H11NHCH2CH2CHV) Prepared according to Example 1l, from avone-7- oxy-acetyl-methylester and cyclohexyl-propylene-diamine. M.P. 8385 C.:

CasHzoOiNz Theory N, 6.61% Found N, 6.65%

(b) The hydrochloride (M.P. 236238 C.) was also prepared as per Example l1. The avone-7-oxy-acety1- (N-methyl-piperazine)-amide (R and R1 plus the N atom forming N-methylpiperazine) i /C\ /C\ cnr-CH, "1 (iHv-N NC0CH20 C -Cem \CHz-C z C/ \O/ was prepared in the same way. M.P. of the base C2zH2204N2 Theory N, 7.55%

Found N, 7.67%

diluted with some dry benzol'.

I amino-propylene)amide (method B) 0.1 ml. flavone 7oxyacetylchloride are suspended in dry benzol. To this is slowly added, while stirring and cooling, 0.1 mol gamma-dimethylaminopropylenediamine The .mixture is now reuxedfor a 4few hours.. Upon cooling crystals deposit. They are filtered olf and washed with a little alcohol. The free base M.P. 136-l40 C.:

CnHasOtNz Theory N 7.03% xFound '.j. N, 7.15%

(e) Hydroch'loride, M.P. ZIO-212 C. Flavone-7-oxyf acetyl(beta-dimenthylaminoethylene)-amide i CzxHzzQiNz Theory N, 7.83% Found N, 7.79%

. 8 M.P. of free base 93-95 C.:

C2'IHS4O4N2 i 1.1"

Theory N, 6.36% Found N, 6.44%

(g) Flavone 7 Oxy-acetyl-(beta-n-dipropylaminoethylene)amide (R=H R1=(I1-CaH'1)2N-CHzCHz-) M.P. of free base 98-100 C.:

CzsHaoOeNz Theory N, 6.79% Found N, 6.82%

The foregoing is to be considered as generally and particularly descriptive of the nature and scope of the present invention without being exhaustive.

What is claimed is:

l. A compound of the formula where R and R1 are selected from the group consisting of H, alkyl, cyclohexyl, cyclohexylaminoalkyl, phenylalkyl, phenylalkoxy, phenylalkoxyamino, hydroxyalkyl, hydroxyphenyl, alkoxyalkyl, dialkylaminoalkyl and antipyrinyl, and when taken with the nitrogen atom, R and R1 form groups selected from the group consisting of morpholine, pyrrolidine, piperidine, alkyl piperidine, and tetramethyl piperidine, and the acid addition and methyl quaternary salts of said compounds, wherein 'R1 and Rz include tertiary amine groups, alkyl and alkoxy groups in every case consisting of those selected from the groups having from one through four carbon atoms.

2. Flavone-7-oxy-acetie acid amide.

3. Flavone-7-oxy-acetic acid N-diethylamide.

4. Flavone-7-oxy( acetic acid-(N-beta dimethylamino) ethylester hydrochloride.

5. Flavone-7-oxy-acetic acid-(beta-diethylamino-ethylene)-amide.

6. Flavone-7-oxy-acetyl-(N-phenylisopropyl)-amide.

7. F1avone-7-oxy-acetyl-(p-ethoxyphenyl)-amde No references cited. 

1. A COMPOUND OF THE FORMULA
 2. FLAVONE-7-OXY-ACETIC ACID AMIDE. 